Deoxyuridine triphosphatase (hereinafter, also referred to as dUTPase (EC3.6.1.23)) is a preventive DNA repair enzyme. This enzyme specifically recognizes only deoxyuridine triphosphate (hereinafter, referred to as dUTP) among canonical nucleoside triphosphates and hydrolyzes dUTP to deoxyuridine monophosphate (hereinafter, referred to as dUMP) and pyrophosphate (Non-Patent Document 1). The enzyme is thought to be responsible for two reactions, (1) decreasing the amount of the intracellular dUTP pools to prevent the misincorporation of uracil instead of thymine into DNA and (2) supplying a substrate dUMP for thymidylate synthase responsible for an important de novo pathway for thymine supply into DNA (Non-Patent Document 2).
dUTPase is known to be an essential enzyme for cell viability in both prokaryotes and eukaryotes. It has thus been suggested that this enzyme can be a target for antitumor drugs (Non-Patent Documents 3 and 4), antimalarial drugs (Patent Document 1 and Non-Patent Document 5), antituberculosis drugs (Non-Patent Document 6), anti-Helicobacter pylori drugs (Patent Document 2), antiparasitic drugs for trypanosoma, leishmania, or the like (Non-Patent Document 7), and antiviral drugs for herpesvirus (e.g., human herpes simplex virus, cytomegalovirus, or Epstein-Barr virus) (Non-Patent Document 8), vaccinia virus (Non-Patent Document 9), or the like.
Thus, dUTPase has been paid attention as a target for therapeutic agents against various diseases, and dUTPase inhibitors have also been studied widely.
For example, a low-molecular compound that mimics dUTP (e.g., Patent Document 3 and Non-Patent Document 10) and a 5′-O-substituted phenyl-deoxyuridine compound (Non-Patent Document 11) are known as the dUTPase inhibitors. However, none of these compounds has sufficient inhibitory activity against human dUTPase and is available as a medicament.
Therefore, the development of the potent human dUTPase inhibitors which are useful as therapeutic agents for disease associated with dUTPase, for example, an antitumor drug, are urgently required.